Hits Keep Coming in the Fight Against Multiple Sclerosis

Mr. Susman is a freelance medical writer based in Florida, USA. He travels worldwide to report from medical conferences, writing regularly for wire services, internet websites, and medical journals such as the Journal of the National Cancer Institute and AIDS.

For comments, edwardsusman@cs.com

NEW ORLEANS, Louisiana – In the past 15 years, more than a dozen new drugs – mainly targeted biologic agents – have been rolled out in the fight to control and possibly change the natural history of relapsing remitting multiple sclerosis, and at the annual meeting of the Consortium of Multiple Sclerosis Centers more promising agent were reported.

Treatment with the investigative agent ublituximab quickly and effectively achieved its goal of wiping out populations of CD19-positive B cells among individuals with multiple sclerosis, said Amy Lovett-Backe, PhD, professor of microbial infection and immunity at the Ohio State University, Columbus.

“Ublituximab efficiently depletes 99% of B cells, meeting the endpoint of the greater than 95% depletion within 2 weeks of the second dose, comparable to ocrelizumab (Orcevus),” she said in her oral presentation. On the other hand, T-cell populations dipped a bit after patients took ublituximab but then remained stable through 24 weeks of therapy.

Ublituximab is a novel chimeric monoclonal antibody targeting a unique epitope on the CD20 antigen, and is glycoengineered to enhance affinity for all variants of receptors, thereby demonstrating greater antibody-dependent cellular cytotoxicity activity than rituximab and ofatumumab, Dr. Lovett-Racke said.

Ublituximab has been used in trials in which it has targeted cancer, but for its use in multiple sclerosis, the dosing has been reduced, she explained. In the trial, there was a built-in 4-week period in which 6 patients were given placebo; after that initial period the placebo patients were given ublituximab.

The difference in the cohorts was infusion time to see how quickly the infusions could be given while maintaining safety. The researchers studied 60 minute; 90 minute and 3 hour infusions schedules. The initial dose for ll the patients in the study was 4 hours. Then at the time for the second dose at day 15, the infusion times were shorter. During the first 2 weeks the each person on the active agent was receiving 450 mg of ublituximab. For the 24 week dose, the infusion time was shortened again to 1 hour to 1.5 hours.

The Phase II study enrolled 24 patients in a variety of infusion times and included a placebo group that was later crossed over to receiving ublituximab. The patients were about 40 years of age; 67 percent were women and they patients had mean duration of time with multiple sclerosis of 8.8 years.

During the placebo run-in phase of the trial about 5 percent to 10 percent of B cells are in the peripheral blood. “That is pretty normal levels of B cells,” Dr. Lovett-Racke said. She illustrated how one patients with a normal level of B cells at the start of the treatment phase of the study show a “complete loss of B cells within just 24 hours of treatment. And this loss is maintained through the initial 4 week period” of analysis.

Patients who began the study on placebo, showed fluctuating B cells counts until they were switched over to ublituximab therapy, and then their B cell levels dropped to virtually 0 almost overnight.

“After 2 days of treatment with ublituximab the B cell counts have effectively dropped to 0 and remains at that level through week 4 for all the cohorts no matter what their initial therapy was or how long the infusions took to deliver the drugs.

Another new drug

Another new agent, called CHS-131, also looked promising in Phase II trials. Treatment with agent appears to reduce gadolinium-positive lesions and reduces cortical atrophy in preliminary Phase II trials, reported David Weinstein, MD, PhD, chief scientific officer and chief medical officer of InteKrin Therapuetics of Redwood City, Calif., the developer of the drug.

A 3mg daily of CHS-131, an oral modulator of peroxisome proliferator activated receptor (PPAR-gamma), was associated with reduced contrast-enhancing lesions of 52 percent over a 6-month period compared with placebo,

In his poster presentation, Dr. Weinstein reported that among the 69 evaluable patients assigned to placebo there was a mean of 7.8 new lesions; among the 70 patients assigned to the 1 mg dose of CHS-131 there was a mean of 7.6 new contrast-enhancing lesions; among the 70 patients assigned to CHS-131 at the 3 mg dose there was a mean of 4.2 new lesions (P=0.003).

He also illustrated that in cortical volume loss from baseline, the reduction after 6 months was 1.1 percent among patients on placebo and was 0.7 percent among patients on CHS-131 – a 34.2 percent reduction in loss. The extent of atrophy loss between placebo and the 1 mg dose was not significantly different.

“We are continuing to do more studies with this agent,” he said. “We would like to try a higher dose, perhaps 5 mg or 6 mg. We believe this drug crosses the blood brain barrier and may exert potent anti-inflammatory effects in the central nervous system.”

The study was conducted in Russia among multiple sclerosis who were naïve to treatment and had been diagnosed with the relapsing-remitting form of the disease within the last 3 years. All of the patients had an Expanded Disability Status Scale of 6 or less at the time of screening. They were required to have had at least one contrast-enhancing lesion during the previous 12 months and had to have less than 10 contrast-enhancing lesions at the time of screening.

The mean age of the subject who received CHS-131 was 30 years; the mean age of the placebo patients was 31 years. The patients given were CHS-131 were 60.5% women; the placebo patients were 74.3 percent women. All the patients in this study were Caucasian. Their mean scores on the Expanded Disability Status Scale was 2.2.

Maybe it’s not MS

More than 30 percent of patients sent to a tertiary clinic with a diagnosis of multiple sclerosis turned out to have something other than the disease. Of 93 consecutive patients referred to a multiple sclerosis specialty clinic, re-evaluation found that 31 of these individuals did not have multiple sclerosis after all, said Marwa Kaisey, MD, a multiple sclerosis neuroimaging fellow at the University of California at Los Angeles and at Cedars-Sinai, Los Angeles.

“Neurologists and multiple sclerosis specialist especially should re-evaluate and existing multiple sclerosis diagnosis rather than taking it at face value given the high rate of misdiagnoses,” Dr. Kaisey said at her poster presentation.

In her study, she and colleagues evaluated patients who were sent to her specialty center to confirm a diagnosis of multiple sclerosis so the patient could begin disease modifying therapy. “these were all patients who visited a neurologist who thought the patients had multiple sclerosis,” Kaisey said. “We found that 33 percent had a misdiagnosis.” Among those misdiagnoses were patients who were having migraines, some had spine disease, and others had brain white matter ischemic disease.

She said that 16 percent of the suspected multiple sclerosis patients turned out to have migraines; 13 percent of the patients had spine spondylosis and 13 percent had white matter ischemic disease. There were also multiple sclerosis diagnoses that turned out to be cerebral palsy, scleroderma complicated by neuropathy, hereditary muscular disease, fibromyalgia, optic neuritis, uveitis, headache and anxiety. The patients ranges in age from 22 years to 69 years.

“There were no cases of purely psychiatric disease without underlying neurology,” Kaisey said. She said that recent imaging studies and lumbar puncture-related tests were most likely the examinations that were able to differentiate the multiple sclerosis patients from those with misdiagnoses.

“The really disturbing part is that 10 percent of the patients with the wrong diagnosis had been started on disease modifying agents for multiple sclerosis,” Dr. Kaisey said.

“I tell patients who are referred to us that there is no one test that can determine if you have multiple sclerosis. It’s not like a pregnancy test where you either are or are not,” she said. “The diagnosis of multiple sclerosis involves evaluation of the patient history, examination, imaging and ancillary testing. Many diseases mimic to often vague symptoms of multiple sclerosis and cause white matter lesions in the central nervous system. We have to put together the whole picture and come up with the best diagnosis.”

She said that one of the first steps she takes with a referred patients is to redo an MRI. “Some of the patients we have bring us MRIs that are 4 years old or more,” she said.